Improvement of dissolution properties of a new Helicobacter pylori eradicating agent (TG44) by inclusion complexation with β-cyclodextrin

Abstract

The interaction of a newly developed Helicobacter pylori eradicating agent (TG44, 4-methylbenzyl-4′-[trans-4-(guanidinomethyl)cyclohexylcarbonyloxy] biphenyl-4-carboxlylate monohydrochloride) with β-cyclodextrin (β-CyD) in aqueous solution and in solid state was studied to gain insight into the high in-vivo H. pylori eradicating activity of TG44/β-CyD complex. The interaction was studied by the solubility method, spectroscopic methods, powder X-ray diffractometry and differential scanning colorimetry (DSC). TG44 gave AL-type phase solubility diagram with β-CyD in water, showing a linear increase in solubility of the drug up to 8mM β-CyD concentration. The solubility of TG44 (0.04 mM in water at 25°C) increased about 70-folds at 8 mM β-CyD. Ultraviolet, circular dichroism, fluorescence and 1H-nuclear magnetic resonance spectroscopic studies indicated that TG44 forms the inclusion complex with β-CyD in a 1:1 stoichiometry and the biphenyl moiety of TG44 is preferably included in the β-CyD cavity in water. The Giordano plot made by monitoring changes in the fusion enthalpy of TG44 (about 184°C) suggested that TG44 forms the 1:1 complex with β-CyD in the solid state. The TG44/β-CyD solid complex in a 1:1 stoichiometry was prepared by the grinding and spray-drying methods and confirmed by powder X-ray diffractometry and DSC that the complex is in an amorphous state. The initial dissolution rate of TG44/β-CyD complex was significantly faster than those of the drug alone and the physical mixture of both components, maintaining higher supersaturated concentrations of the drug for a long time. The results suggested that the higher eradicating activity of TG44/β-CyD complex to Helicobacter pylori, compared with that of the drug alone, is attributable at least partly to the faster dissolving property of the complex and its ability to maintain the supersaturated state of the drug in the gastric fluid. © 2007 Pharmaceutical Society of Japan.